One-carbon homologation of alkenes

Abstract

One-carbon homologues are structurally related and functionally identical organic molecules whose chain lengths differ by a single methylene (-CH₂-) unit¹. Across many classes of molecule-including pharmaceutical agents, natural products, agrochemicals, fragrances and petroleum products-the physicochemical characteristics exhibited by members of a homologous series subtly differ from one compound to another, which can impart remarkable differences to their function². The efficient generation of homologues is, therefore, an important strategy in molecular discovery programmes^3,4. Despite the availability of homologation strategies for several functional groups^5,6, direct and general methods for one-carbon chain extension in alkenes remain an unmet synthetic need^7,8. Here we report a catalytic one-carbon homologation process that is effective for many classes of alkene in simple and complex molecules. By leveraging the intrinsic reactivity of a new multifaceted allylsulfone reagent, a streamlined one-pot process, involving cross-metathesis and a fragmentation-retro-ene cascade, formally inserts a single methylene unit into the alkene chain. Among the applications of this process to several structurally and functionally complex molecules, we demonstrate how this practical transformation generates previously unexplored homologues of cyclosporine A⁹. These homologues exhibit modulated pharmacological and biological properties and could provide promising leads as cyclophilin inhibitors, a target that has great potential in many disease areas¹⁰.

Fig. 1. Evolution of a strategy for one-carbon alkene homologation.

a, The effect of homologues on biological activity: side chain length compared with immunosuppressive activity in a family of natural products. b, Homologation processes for common functional groups. c, Generally adopted sequence for alkene homologation. d, Design plan for a catalytic one-carbon alkene homologation process.

Fig. 2. Development of a one-carbon alkene-homologation process.

a, Optimized conditions for the one-pot alkene homologation process. b, Scope of monosubstituted alkenes. c, Natural products and bioactive molecules. AY, assay yield (¹H NMR); ^‡based on recovered starting material.

Fig. 3. One-carbon alkene homologation of architecturally complex molecules.

a, One-carbon homologation of the vinyl ACCA motif, common to many antiviral drugs. b, Streamlined one-carbon homologation of the alkene side chain in tacrolimus and its comparison to a stepwise synthesis.

Fig. 4. Homologation of disubstituted alkenes.

a, Chain extension of 1,1-disubstituted alkenes with 1CTR 1b and scope. b, Homologation of 1,2-disubstituted alkenes and application to feedstock upgrading. c, Two-carbon homologation of terminal alkenes: introduction of carbons into the alkene chain and at double-bond terminus. d, Experiments to explore the E/Z selectivity of the retro-ene process. e, Ring expansion of macrocycles. AY, assay yield (¹H NMR).

Fig. 5. Homologation of cyclosporine A and biological evaluation of its corresponding homologues.

a, Iterative one-carbon homologation of cyclosporine A (CsA). b, IL-2 release from Jurkat T cells for CsA, 21 and 22 (center values represent the means of three replicates; error bars represent s.e.m.). c, Biochemical assay for calcineurin inhibition for CsA, 21 and 22 (assays were performed in duplicate, with IC₅₀ values calculated from mean averages).

Fig. 6. Synthesis of new cyclosporine A analogues and their biological evaluation.

a, Exploiting the modularity of the 1CTR for side chain functionalization. b, Contra-thermodynamic isomerization of cyclosporine A (CsA) and its homologation to homoisocyclosporine. c, Biochemical assays for calcineurin inhibition and cyclophilin binding for compounds 21–26 (assays were performed in duplicate, with IC₅₀ and K_d values calculated from mean averages).